Parent Award ? K01AG043581 ? Race, Childhood Social Disadvantage, and the Adult Brain Project Summary (K01 Parent Grant) The objective of the present career development plan is to launch the candidate?s independent research career investigating the mechanisms by which racial disparities in exposure to early life social disadvantage (ELSD) promote accelerated subclinical and clinical brain pathology in African Americans (AA) across the life course. There are pronounced AA-White disparities in brain health endpoints including stroke, dementia, and cognitive decline. Recent data suggest that earlier disparities in brain health are also noted on magnetic resonance imaging (MRI). Exposure to greater ELSD ? characterized by harsher residential and neighborhood environments and lower parental socioeconomic status (SES) ? may chart a course towards an accelerated onset of, and more severe, brain pathology observed in AAs as characterized by multiple MRI-assessed indicators of subclinical brain pathology including lower gray matter (GM) volumes, greater white matter lesion volumes (WMLV) and lesser WM integrity. This K01 will allow the candidate to extend her prior training on the relation of psychosocial factors to coronary heart disease risk among adolescent and early to midlife AAs by providing training in (a) the life course perspective and accelerated theories of aging, particularly as applied to racial disparities in social disadvantage and health, and (b) the brain and related vasculature, and MRI indicators of brain pathology including subclinical cerebrovascular disease. The present project is a substudy to the HANDLS SCAN project ? itself an ancillary study to the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, a 20-year epidemiological investigation conducted by the NIA Intramural Research Program that assesses health disparities in 3,720 AA and White adults (ages 30-64 at baseline) living in Baltimore, MD. In 250 HANDLS participants, HANDLS SCAN examines the relations of race and adult SES to MRI-indicators of subclinical brain pathology that may underlie risk for stroke, dementia, and cognitive and functional decline. These 250 HANDLS SCAN participants will participate in a call-back to complete measures of ELSD. We will determine: (a) whether ELSD is related to MRI-indicators of brain pathology predictive of future stroke, cognitive, and functional decline, and whether these associations are more pronounced in AAs than in White adults, and (b) explore potential psychosocial, behavioral, and biomedical mediators of these associations. The interdisciplinary training outlined in this application will allow the candidate to carve out a unique and unmatched research program that is desperately warranted by the pronounced prevalence of cerebrovascular and other brain disease in AAs. The interrelations among life course social disadvantage, accelerated aging, and brain health endpoints have been grossly understudied, and are crucial to developing appropriate prevention and intervention strategies geared toward reducing and ultimately eliminating race-related health disparities in brain aging. CURRENTLY PROPOSED ADMINISTRATIVE SUPPLEMENT The proposed work builds upon the parent award K01 study emphasis on ELSD, and our novel recent findings demonstrating an association of individual- level discrimination with greater WMLV among older AAs in HANDLS SCAN (Beatty Moody et al. in press; 1). Here, we ask whether exposure to adult social disadvantage, indexed by an aggregate of neighborhood level measures of structural (or institutional-level) discrimination ? residential segregation assessed by the ratio of the numbers of White versus AA residents, % of population employed, with high school diploma/equivalency, and in poverty ? are linked to MRI-assessed WMLV, total gray matter (GM) and white matter (WM) volumes, total brain volume (TBV), among 206 AA and White HANDLS SCAN participants. We will also examine whether these associations (a) are moderated by self-identified race; and (b) are mediated (or further moderated) by cumulative exposure to several forms of individual-level discrimination (i.e., one-on-one experiences of bias) including unfair treatment, racial discrimination, and lifetime burden. The proposed project extends a 2014 study (2) in which state-level employment status and educational attainment, conceptualized as markers of structural racism as they index ?systematic exclusion of Blacks from resources and mobility in society,? were linked to greater incidence of myocardial infarction among AAs, but lower incidence in Whites. In addition to individual-level discrimination measures from HANDLS, data from the 2000 U.S. Census have been matched to geocoded HANDLS baseline data to provide the structural discrimination measures of interest. MRI data were obtained in HANDLS follow-up approximately 5-6 years later providing the data to examine whether exposures to structural and individual-level discrimination are associated with subclinical brain pathology.